Developing a Ruthenium(III) Complex to Trigger Gasdermin E-Mediated Pyroptosis and an Immune Response Based on Decitabine and Liposomes: Targeting Inhibition of Gastric Tumor Growth and Metastasis.

To develop next-generation metal drugs with high efficiency and low toxicity for targeting inhibition of gastric tumor growth and metastasis, we not only optimized a series of ruthenium (Ru, III) 2-hydroxy-1-naphthaldehyde thiosemicarbazone complexes to obtain a Ru(III) complex (4b) with remarkable cytotoxicity in vitro but also constructed a 4b-decitabine (DCT)/liposome (Lip) delivery system (4b-DCT-Lip). The in vivo results showed that 4b-DCT-Lip not only had a stronger capacity to inhibit gastric tumor growth and metastasis than 4b-DCT but also addressed the co-delivery problems of 4b-DCT and improved their targeting ability. Furthermore, we confirmed the mechanism of 4b-DCT/4b-DCT-Lip inhibiting the growth and metastasis of a gastric tumor. DCT-upregulated gasdermin E (GSDME) was cleaved by 4b-activated caspase-3 to afford GSDME-N terminal and then was aggregated to form nonselective pores on the cell membrane of a gastric tumor, thereby inducing pyroptosis and a pyroptosis-induced immune response.

Developing a Gadolinium(III) Compound Based on Apoferritin for Targeted Magnetic Resonance Imaging and Dual-Modal Therapy of Cancer.

To integrate targeted diagnosis and treatment of cancer, we proposed to develop a gadolinium (Gd) agent based on the properties of apoferritin (AFt). To this end, we not only optimized a series of Gd(III) 8-hydroxyquinoline-2-carboxaldehyde-thiosemicarbazone compounds to obtain a Gd(III) compound (C4) with remarkable T1-weighted magnetic resonance imaging (MRI) performance and cytotoxicity to cancer cells in vitro but also constructed an AFt-C4 nanoparticle (NP) delivery system. Importantly, AFt-C4 NPs improved the targeting ability of C4 in vivo and showed enhanced MRI performance and tumor growth inhibition ratio relative to C4 alone. Furthermore, we confirmed that C4 and AFt-C4 NPs inhibited tumor growth through apoptosis, ferroptosis, and ferroptosis-induced immune response.

Developing an Anticancer Platinum(II) Compound Based on the Uniqueness of Human Serum Albumin.

To develop the next-generation Pt drug with remarkable activity and low toxicity to maximally inhibit tumor growth, we optimized a Pt(II) thiosemicarbazone compound (C4) with remarkable cytotoxicity to SK-N-MC cells and then constructed a new human serum albumin-C4 (HSA-C4) complex delivery system. The in vivo results showed that C4 and the HSA-C4 complex have remarkable therapeutic efficiency and almost no toxicity; they induced apoptosis and inhibited tumor angiogenesis. This system showed potential as a practical Pt drug. This study could pave the way for developing next-generation dual-targeted Pt drugs and achieving their targeting therapy for cancer.

Developing a Gallium(III) Agent Based on the Properties of the Tumor Microenvironment and Lactoferrin: Achieving Two-Agent Co-delivery and Multi-targeted Combination Therapy of Cancer.

To develop a next-generation anticancer metal-based drug, realize the multi-targeted combination therapy of protein drug and metal-based drug for cancer, solve their co-delivery challenges, and improve their in vivo targeting ability, we proposed to develop a multi-targeted anticancer metal-based agent exploiting the properties of the tumor microenvironment (TME) and of lactoferrin (LF). To this end, we optimized a series of gallium (Ga, III) isopropyl-2-pyridyl-ketone thiosemicarbazone compounds to obtain a Ga compound (C4) with remarkable cytotoxicity and then constructed a new LF-C4 nanoparticle (LF-C4 NP) delivery system. In vivo studies showed that LF-C4 NPs not only had a greater capacity for inhibiting tumor growth than LF or C4 alone but also solved the co-delivery problems of LF and C4 and improved their targeting ability. Furthermore, free C4 and LF-C4 NPs inhibited tumor growth through multiple synergistic actions on the TME: killing cancer cell, inhibiting tumor angiogenesis, and activating immune system.

Current status of iridium-based complexes against lung cancer.

Lung cancer is one of the most common malignant tumors, with the highest mortality rate in the world, and its incidence is second only to breast cancer. It has posed a serious threat to human health. Cisplatin, a metal-based drug, is one of the most widely used chemotherapeutic agents for the treatment of various cancers. However, its clinical efficacy is seriously limited by numerous side effects and drug resistance. This has led to the exploration and development of other transition metal complexes for the treatment of malignant tumors. In recent years, iridium-based complexes have attracted extensive attention due to their potent anticancer activities, limited side effects, unique antitumor mechanisms, and rich optical properties, and are expected to be potential antitumor drugs. In this review, we summarize the recent progress of iridium complexes against lung cancer and introduce their anti-tumor mechanisms, including apoptosis, cycle arrest, inhibition of lung cancer cell migration, induction of immunogenic cell death, etc.

Design of a novel Pt(II) complex to reverse cisplatin-induced resistance in lung cancer via a multi-mechanism.

In order to develop a novel platinum (Pt) complex aiming to overcome cisplatin resistance, we synthesised a series of novel Pt complexes (C1-C6). These Pt complexes displayed potent cytotoxicity activity against resistant lung cancer cells (A549cisR) in vitro and efficiently inhibited tumour growth in vivo. The Pt complexes can target DNA, lead to DNA platination and cause cell cycle arrest in the S phase, thus impeding precise DNA synthesis. C6, in particular, induced not only apoptosis but also lethal autophagy in A549cisR cells. In addition, these novel Pt complexes reversed cisplatin-induced resistance via inhibiting the expression of P-glycoprotein and decreasing the level of glutathione in A549cisR cells. Moreover, the ERK pathway was involved in C6-induced overcoming cisplatin resistance.

Developing a Novel Indium(III) Agent Based on Human Serum Albumin Nanoparticles: Integrating Bioimaging and Therapy.

To effectively integrate diagnosis and therapy for tumors, we proposed to develop an indium (In) agent based on the unique property of human serum albumin (HSA) nanoparticles (NPs). A novel In(III) quinoline-2-formaldehyde thiosemicarbazone compound (C5) was optimized with remarkable cytotoxicity and fluorescence to cancer cells in vitro. An HSA-C5 complex NP delivery system was then successfully constructed. Importantly, the HSA-C5 complex NPs have stronger bioimaging and therapeutic efficiency relative to C5 alone in vivo. Besides, the results of gene chip analysis revealed that C5/HSA-C5 complex NPs act on cancer cells through multiple mechanisms: inducing autophagy, apoptosis, and inhibiting the PI3K-Akt signaling pathway.

Developing a Novel Indium(III) Agent Based on Liposomes to Overcome Cisplatin-Induced Resistance in Breast Cancer by Multitargeting the Tumor Microenvironment Components.

To overcome the resistance of cancer cells to platinum-based drugs and effectively suppress tumor growth, we developed a novel indium (In) agent based on liposomes (Lips). Thus, we not only obtained an In(III) thiosemicarbazone agent (5b) with remarkable cytotoxicity by optimizing a series of In(III) thiosemicarbazone agents (1b-5b) but also successfully constructed a novel 5b-loaded Lip (5b-Lip) delivery system. Importantly, in vitro and in vivo results revealed that 5b/5b-Lip overcame the tumor cell resistance and effectively inhibited MCF-7/DDP tumor growth. In addition, Lips improved the intracellular accumulation of 5b. We also confirmed the mechanism by which 5b/5b-Lip overcomes breast cancer cell resistance. 5b/5b-Lip cannot act against DNA in cancer cells but attacks the two cell components in the tumor microenvironment, namely, by inducing apoptosis and lethal autophagy of cancer cells and resetting tumor-promoting M2 macrophages to the tumor-killing M1 phenotype.

Development of a multi-target anticancer Sn(ii) pyridine-2-carboxaldehyde thiosemicarbazone complex.

In this study, we proposed to design effective multi-target anticancer agents based on the chelation of nontoxic metals with ligands that possess anticancer activity. In total, five Sn(ii) pyridine-2-carboxaldehyde thiosemicarbazone complexes are synthesized and their activities are tested. Among these complexes, C5 is found to show the highest cytotoxicity on investigating their structure-activity relationships. In addition, C5 not only exhibits an effective inhibitory effect against tumor growth in vivo, but also suppresses angiogenesis and restricts the metastasis of cancer cells in vitro. Multiple mechanisms underlie the antitumor effect of C5, and they include acting against DNA, inducing apoptosis, and inhibiting the activities of anti-apoptotic Bcl-xL protein, metalloproteinase MMP2 and topoisomerase II.